New Lipid Lowering Agents (PCSK9 Inhibitors, Bempedoic Acid, Apabetalone) in the Elderly? The State of the Recent Knowledge Prof.

Transcription

1 New Lipid Lowering Agents (PCSK9 Inhibitors, Bempedoic Acid, Apabetalone) in the Elderly? The State of the Recent Knowledge Prof. Maciej Banach Łódź, PL

2 According to : Central Intelligence Agency". Retrieved ; updated 2016.

3 According to: Wall chart on Population Ageing and Development 2012 (United Nation Population Devision)

4 According to: Wall chart on Population Ageing and Development 2012 (United Nation Population Devision)

5 POLSENIOR cohort study (2011) Hypercholesterolemia ( 190 mg/dl) prevalence in the elderly ( 65) in Poland 56% 66% 62% All patients 65+ M W Together Bledowski P., et al. Exp Gerontol Dec;46(12):

6 Total cholesterol levels depending on sex and age W W Proportion of patients prescribed cholesterol lowering drugs and mean cholesterol concentration of treated and untreated patients (treatment-risk paradox) Sheppard J P et al. BMJ 2012;345:bmj.e4535 Bledowski P., et al. Exp Gerontol Dec;46(12):

7 All-cause mortality and cholesterol in the elderly Low TC (<5.5 mmol/l / 213 mg/dl) is associated with increased mortality among 80+-year olds. There was no clear optimal level of cholesterol in 80+-year-old people. Some studies found the intermediate level of the cholesterol (around 6 mmol/l / 232 mg/dl) to be associated with the lowest mortality, but this was not consistent. Few data on TC and mortality are available on 80+-year olds. Petersen L K et al. Age Ageing 2010;39:

8 PoLA/CFPiP/PCS Guidelines for the Management of Dyslipidaemias for Family Physicians 2016 Banach M, et al. Arch Med. Sci 2017;13(1):1-45.

9 Waterfall plot for individual trial participants allocated to rosuvastatin 20 mg for the per cent change in low-density lipoprotein cholesterol (left) and concordant incident event rates (per 1000 person-years) for the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin primary endpoint (right). Paul M Ridker et al. Eur Heart J 2016;eurheartj.ehw046 Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oup.com.

10 Jackievicius C, et al. JAMA 2002;288(4):

11 Kutner J.S., et al. JAMA Intern Med May; 175(5):

12 CV Event Rate (%) We Need a Drug that Helps High-risk Patients to Achieve LDL-C Goal (1.0) LDL-C goal* 60 (1.6) 80 (2.1) Patient receives PCSK9 inhibitor Patient adds XXX 60% reduction in LDL-C Patient adds ezetimibe 15% reduction in LDL-C 100 (2.5) 120 (3.1) 140 (3.6) Patient receives first statin 35% reduction in LDL-C Patient titrates statin LDL-C Achieved, mg/dl (mmol/l) 8% reduction in LDL-C 160 (4.1) 180 (4.7) Illustrative High-risk patient first diagnosed With statin intolerance 200 (5.2) *LDL-C goal for high-risk and very high-risk patients as defined by ESC/EAS guidelines for the management of dyslipidemias. Reiner Z, et al. Eur Heart J 2011;32:

13 Conditions and Populations at High Risk of Statin Intolerance Liver diseases ALT > 3x ULN occurs in < 0.5% for moderatedose statins and rosuvastatin at all doses, and about 1% for 80 mg of atorvastatin or simvastatin. However, this might be an overstatement because, in most studies, the incidence of ALT increase was similar in statin and placebo patients, and because almost 50% of dyslipidaemic patients requiring statin treatment might have had established NAFLD. Elderly patients CKD Rheumatic diseases Banach M, et al. Arch Med Sci 2015;11:1 23. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD, chronic kidney disease; CLD, chronic liver disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; KDIGO, Kidney Disease: Improving Global Outcomes; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cirrhosis.

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16 Changes in the proportion of individuals in different LDL-C ranges between the studies performed in 2004, 2006 and LIPIDOGRAM2015 cohort study % 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% LDL<=70 (70-100] ( ] ( ] ( ] LDL>190 Based on the analysis of patients we found 199 patients with LDL-C 330 mg/dl (8 pts.) (including 31 patients with positive clinical personal history of premature CAD - 10 pts. in total), and 228 subjects with LDL-C: mg/dl and positive clinical personal history of premature CAD (7 pts. in total in DLCN criteria). The estimated overall prevalence of probable/definite FH ( 7 pts.) was 1,27% or 1 in 79, suggesting 400,457 Polish adults with FH or at the high risk of FH diagnosis.

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21 LS mean (SE) % change in calculated LDL-C from baseline to Week 24 Change in LDL-C from Baseline to Week 24 According to HeFH status (ITT) Alirocumab Placebo 20 HeFH population Non-HeFH population LS mean difference vs. placebo: -56.3±1.9% 7.0±2.4% -0.5±1.1% 63.2% -62.1±0.8% Interaction p-value % 21

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28 Percent change in LDL-C for (a) Placebo-controlled and (b) Ezetimibe-controlled studies by Age

29 Percent change in ApoB for (a) Placebo-controlled and (b) Ezetimibe-controlled studies by Age

30 Percent change in TC for (a) Placebo-controlled and (b) Ezetimibe-controlled studies by Age

31 Percent change in Lp(a) for (a) Placebo-controlled and (b) Ezetimibe-controlled studies by Age

32 Adverse Events (Parent Studies) Koren MJ, et al. ACC 2015 presentation.

33 Adverse Events (Extension Studies) PCSK9 inhibition with evolocumab potently reduced LDL-C and other atherogenic lipid parameters in patients 65 or 75 years old. The incidence of adverse events in the elderly population was comparable between those receiving evolocumab or control. Koren MJ, et al. ACC 2015 presentation.

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35 ETC-1002: PHASE 2 CLINICAL STUDIES Study Number Short Title (N=total/ETC-1002 treated) Phase 2a in Patients with Hypercholesterolemia (N=177/133) Phase 2a in Patients with Hypercholesterolemia and Type 2 Diabetes (N=60/30) Phase 2a in Patients with Hypercholesterolemia and a History of Statin Intolerance (N=56/37) Phase 2a in Patients with Hypercholesterolemia Added-on to Atorvastatin 10 mg (N=58/42) Phase 2b in Patients with Hypercholesterolemia with or without Statin Intolerance vs. Ezetimibe (N=349/249) Phase 2b in Patients with Hypercholesterolemia while on Stable Statin Therapy (N=134/88) Phase 2a in Patients with Hypercholesterolemia and Hypertension (N=143/72) ' LDL-C Lowering* (pbo corrected) Dose Range (mg) Treatment Duration Up to 27% (25%) 40, 80, Wks 43% (39%) 80, Wks 32% (29%) 22% (22%) Up to 30% (1002) Up to 48% ( ezetimibe) 60, 120, 180, , 120, 180, , 180, ezetimibe, ezetimibe 8 Wks 8 Wks 12 Wks 24% (20%) 120, Wks 21% (24%) Wks *Average LDL-C % Change from Baseline 35

36 Bempedoic Acid Phase 3 CLEAR Program LDL-C Lowering Indication (Total N=~3400): ASCVD and/or HeFH CLEAR Harmony; Long-Term, N=2233 CLEAR Wisdom; High Risk, N= weeks safety 52 weeks safety / 12 weeks LDL-C Open-Label Extension (OLE) 78 weeks safety Statin Intolerant CLEAR Serenity; SI, N=300 CLEAR Tranquility; SI, +EZ, N= weeks safety / 12 weeks LDL-C 12 weeks LDL-C Four (4) pivotal Phase 3 studies designed to enroll ~3400 high risk patients randomized 2:1 At high CV risk with hypercholesterolemia on optimized background lipid-modifying therapy (with ASCVD and/or HeFH) Only able to tolerate less than the lowest approved daily starting dose of a statin and considered statin intolerant Phase 3 program adequate to support approval for an LDL-C lowering indication for bempedoic acid 36

37 Randomization (T1) CLEAR Outcomes ( ) Global CVOT Study Design A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFECTS OF BEMPEDOIC ACID (ETC-1002) ON THE OCCURRENCE OF MAJOR CARDIOVASCULAR EVENTS IN PATIENTS WITH, OR AT HIGH RISK FOR, CARDIOVASCULAR DISEASE WHO ARE STATIN INTOLERANT SP & PP Patients with Elevated LDL-C and Statin Intolerance Bempedoic acid 180 mg (n=6302) Placebo (n=6302) Study Phase Week Study Visit -5 S1 Screen Period -4 S2 Single Blind Placebo Run in 0 T1 Double Blind Treatment Period Evaluating MACE/LDL-C Reduction/Safety ~4.75 years After T1 Visits at months 1, 3 and 6 alternating phone visits and clinic visits every 3 months thereafter 37

38 A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFECT OF BEMPEDOIC ACID (ETC-1002) ON THE OCCURRENCE OF MAJOR CARDIOVASCULAR EVENTS IN PATIENTS WITH CARDIOVASCULAR DISEASE WHO ARE UNABLE TO TOLERATE STATIN THERAPY ( ) STUDY CONCEPT Primary Objective: To evaluate whether bempedoic acid (ETC-1002) 180 mg/day reduces the risk of CV disease in patients with ASCVD who are unable to tolerate statin therapy. Patients with high risk ASCVD and statin intolerance (n=10,000) Allowed background lipid therapies: Approved non-statin drugs or supplements Per definition of statin intolerance, use of less than the approved starting dose of a statin is also permitted if tolerated Baseline LDL-C >110 mg/dl Mean treatment duration ~3 years 38

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